The brain mineralocorticoid receptor:
greedy for ligand, mysterious in function
by
Reul JM, Gesing A, Droste S, Stec IS, Weber A,
Bachmann C, Bilang-Bleuel A, Holsboer F, Linthorst AC
Section of Neuropsychopharmacology,
Max Planck Institute of Psychiatry,
Kraepelinstrasse 2, 80804, Munich, Germany
Eur J Pharmacol 2000 Sep 29; 405(1-3):235-249
ABSTRACTGlucocorticoids exert their regulatory effects on the hypothalamic-pituitary-adrenocortical axis via two types of corticosteroid receptors: the glucocorticoid receptor and the mineralocorticoid receptor. Whereas the glucocorticoid receptor has a broad distribution in the brain, highest levels of mineralocorticoid receptor are found in the hippocampus. Based on the differential occupancy profile by endogenous glucocorticoids, glucocorticoid receptors are thought to mediate negative feedback signals of elevated glucocorticoid levels, whereas mineralocorticoid receptors control the inhibitory tone of the hippocampus on hypothalamic-pituitary-adrenocortical axis activity. Dysfunction of mineralocorticoid receptors and glucocorticoid receptors are thought to be implicated in stress-related psychiatric diseases such as major depression. Because of its intriguing features, we focus in this review on the mineralocorticoid receptor and provide data which reveal novel aspects of the pharmacology and physiology of mineralocorticoid receptors. Newly obtained results are presented, which help to solve the paradox of why dexamethasone binds with high affinity to mineralocorticoid receptors in vitro, yet binds poorly in vivo. Until recently, mineralocorticoid receptor protein and mRNA levels could only be routinely studied with in vitro cytosol binding assays, in vitro and in vivo receptor autoradiography, Northern blot analysis, and in situ hybridization. These methods are unfortunately hampered by several flaws, such as the necessity of adrenalectomy, no or poor neuroanatomical resolution, the fact that mRNA does not provide the same information as protein, or combinations of these factors. We present immunohistochemical data on mineralocorticoid receptors in the brain obtained by using commercially available antibodies, which alleviate many of these shortcomings. Furthermore, an in vivo microdialysis method is presented which allows the assessment of free corticosterone levels in the brain, which is critical for the study of the pharmacological basis of mineralocorticoid receptor (and glucocorticoid receptor) function. Finally, a novel aspect of the regulation of mineralocorticoid receptors is described which provides evidence that this receptor system is dynamically regulated. In conjunction with previously reported effects of antidepressants, these results have initiated a new concept on the cause of the hypothalamic-pituitary-adrenocortical axis disturbances often seen in stress-related psychiatric disorders such as major depression.CRF
LHPA
Stress
HPA Axis
Astressin
Metyrapone
Ketoconazole
Cortisol blues
Corticosteroids
Pharmacogenetics
Cushing's Syndrome
CRH1 receptor antagonists
Stress, depression and anxiety
The corticosteroid hypothesis of depression
Stress, dynorphin, dysphoria and the kappa opioid systemand further reading
Refs
HOME
HedWeb
Nootropics
cocaine.wiki
Future Opioids
BLTC Research
MDMA/Ecstasy
Superhapiness?
Utopian Surgery?
The Abolitionist Project
The Hedonistic Imperative
The Reproductive Revolution
Critique of Huxley's Brave New World
The Good Drug Guide
The Responsible Parent's Guide
To Healthy Mood Boosters For All The Family
